Neisseria gonorrhoeae causes about 600,000 new infections each year in the United States, with health-care costs approaching 2 billion dollars/year. The costs and human suffering are amplified by the fact that concomitant gonococcal infections appear to facilitate HIV transmission. Gonococci preferentially infect the human urogenital tract, and its ability to enter and transcytose this mucosal surface is a chief cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy, and chronic pelvic pain. Various surface components, i.e., lipooligosaccharide (LOS) and opacity proteins (Opa), are important in mediating these diseases. Most studies have used tissue culture models to study the role of individual surface components in the pathogenic process, even though it is likely that multiple components are needed and/or are able to act synergistically. The fact that this pathogen manipulates its outer membrane suggests that such modifications are important in pathogenesis. Nothing is known about possible interactions between the surface molecules, because to date, we have lacked bacterial strains that have invariant, defined surfaces. This has prevented us from developing a comprehensive understanding of the pathogenesis of gonococcal disease. The objective of this proposal is to understand how gonococcal opacity proteins and Iipooligosaccharides interact in the pathogenic process. The central hypothesis of the proposed research is that different variants of these surface antigens are important for the various stages of infection and/or symptom elicitation. We intend to test our hypotheses by pursuing three specific aims: We will determine how various surface structures interact in the invasion process, we will identify which receptors are responsible for binding specific LOS molecules and we will define the signal transduction pathways that are activated in host celIs that are initiated by gonococcal adherence and/or invasion. The proposed research addresses the fundamental problem of how LOS and Opa interact in the disease process. We will define how LOS and Opa variation contribute to disease pathogenesis. The impact on human health is expected to be significant, because the new knowledge will likely make possible new approaches to the prevention and treatment of gonorrhea.